In this competing renewal, we propose to build upon and extend our recent work on endogenous hormones and risk of breast cancer and also to evaluate several new breast cancer hypotheses. In addition, we propose to address a number of new hypotheses in relation to risk of ovarian cancer, a highly lethal cancer in women for which few prospective evaluations of biomarkers have been conducted. To accomplish these aims, we will conduct two nested case-control studies using already collected biologic samples from the Nurses' Health Study (for breast and ovarian cancers), and both the Women's Health Study and Nurses' Health Study II (for ovarian cancer only). Specifically, we will evaluate plasma estrogen metabolites, prolactin (using two blood samples collected 10 years apart), urinary melatonin, and urinary vs. plasma estrone sulfate, all in relation to breast cancer risk. Further, we will evaluate the independent contribution of endogenous sex steroids to the Gall and Rosner individual breast cancer risk prediction models. We also will evaluate plasma insulin like growth factors, androgens, vitamin D, and polymorphisms in both the progesterone receptor and vitamin D receptor in relation to ovarian cancer risk. Our proposed ovarian cancer aims, with 282 cases in plasma analyses and 521 cases in genetic analyses (all with 2 controls per case), will provide either the first or by far the most detailed prospective assessment of these potentially important risk factors. Finally, as a methodologic aim, we propose several pilot studies to evaluate the feasibility of using mass spectrometry technology (SELDI-TOF) in our cohorts to identify plasma protein profiles that predict subsequent cancer risk. Overall, the large size of these cohorts, their prospective design, high follow-up rates, detailed exposure data collected over many years, and the availability of archived plasma, DNA and urine specimens provides a unique opportunity to test a number of hypotheses of public health importance.